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The Journal of Neuroscience, January 25, 2006, 26(4):1088-1097; doi:10.1523/JNEUROSCI.1369-05.2006

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Neurobiology of Disease
Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

Tiina-Kaisa Kukko-Lukjanov,^1,2 Sanna Soini,¹ Tomi Taira,³ Kimmo A. Michelsen,² Pertti Panula,^2,4 and Irma E. Holopainen¹

¹Department of Pharmacology and Clinical Pharmacology, University of Turku, ²Department of Biology, Åbo Akademi University, Biocity, FIN-20520 Turku, Finland, ³Neuroscience Center and Department of Biosciences, and ⁴Neuroscience Center, Institute of Biomedicine/Anatomy, FIN-00014 University of Helsinki, Finland

Correspondence should be addressed to Dr. Irma E. Holopainen, Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland. Email: irma.holopainen{at}utu.fi

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H₁) and histamine 3 (H₃) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 µM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, -fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 µM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H₃ receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H₁ receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H₁ and H₃ receptors.

Key words: epilepsy; histamine; monoamine; neurotoxicity; neuroprotection; confocal microscopy

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Received April 8, 2005; revised Dec. 2, 2005; accepted Dec. 5, 2005.

Correspondence should be addressed to Dr. Irma E. Holopainen, Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland. Email: irma.holopainen{at}utu.fi

This article has been cited by other articles:

				H. L. Haas, O. A. Sergeeva, and O. Selbach Histamine in the Nervous System Physiol Rev, July 1, 2008; 88(3): 1183 - 1241. [Abstract] [Full Text] [PDF]

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